A Quiet Revolution for Those Prone to Nodding Off

Robert Cloud, a lawyer in Cincinnati, has fallen asleep while talking to clients, while eating dinner, even while meeting with a judge.

Mr. Cloud, 58, has suffered for much of his adult life from narcolepsy, a little-understood sleep disorder that afflicts as many as 100,000 to 200,000 Americans. People with the condition are prone to sudden, uncontrollable attacks of intense sleepiness.

They feel exhausted most of the time, and many also experience cataplexy, brief episodes of loss of muscle control that may occur for no apparent reason or be brought on by laughter, anger, embarrassment, excitement or other strong emotions, as well as physical exertion and sexual stimulation.

Mr. Cloud has collapsed from cataplexy while walking down the street, while shopping and while swimming. He once had an attack on an escalator and fell to the bottom, cutting his head on the steps.

But thanks to a few pills a day, Mr. Cloud can lead a normal life. Stimulants help keep him awake, and to prevent cataplexy he takes Xyrem, an experimental medicine containing the compound GHB, which has been infamous as a date-rape drug. Mr. Cloud receives Xyrem as part of a clinical trial; the Food and Drug Administration is expected to decide within the next few months whether to approve it.

''I was in pretty serious shape, but the medication is remarkably effective,'' said Mr. Cloud, who is executive director of the Narcolepsy Network, an advocacy group.

The development of Xyrem, made by Orphan Medical Inc. of Minnetonka, Minn., is just one of several major advances in the understanding and treating narcolepsy.

''The last two years have been tremendous, a complete revolution,'' said Dr. Emmanuel Mignot, a professor of psychiatry at Stanford and director of its Center for Narcolepsy.

In 1999, two research teams, including one led by Dr. Mignot, determined that abnormalities in how the brain processed a neurotransmitter called hypocretin or orexin (the teams identified the same substance but gave it different names) could cause narcolepsy-like conditions in dogs and mice.

The next year, Dr. Mignot's group and a team at the University of California at Los Angeles confirmed the significance of the substance in human narcolepsy.

When they examined the brains of narcoleptics who had died, they found either no cells containing hypocretin, or much lower levels than were found in normal brains.

The researchers concluded that the disorder was likely to be an autoimmune disorder in which something, perhaps a viral infection, caused the body's immune system to destroy the cells that made hypocretin.

Dr. Jerry Siegel, a professor of psychiatry at U.C.L.A., said the recent discoveries suggested that reversing the neurotransmitter deficiency by administering a hypocretin-based medication could be the most effective treatment for narcolepsy.

While much research remains to be done on the best way to accomplish that, Dr. Siegel said, he estimated that a drug could be on the market in five years. He added that a hypocretin-based medicine could also have applications beyond narcolepsy. ''Hypocretin might be able to treat residual sleepiness from insomnia and other disorders, and it also appears to regulate the systems that can lead to depression,'' he said.

Narcolepsy was first described in the late 19th century, when it was thought to be caused by excessive masturbation and repressed homosexuality. More recently, people with narcolepsy have found themselves treated as though they have a psychological rather than a medical disorder.

''Not only do narcoleptics have a debilitating disease, they're often secondarily victimized because people assume they've been out partying all night,'' Dr. Siegel said.

Some patients say that even their own relatives trivialize the disorder and nag them with useless advice about eating better or exercising more. In addition to a lack of societal support, narcoleptics often have a hard time successfully completing their academic studies or working under any but the most low-pressure conditions. Unless treatment tames the symptoms, driving a car can be dangerous.

An error has occurred. Please try again later.

You are already subscribed to this email.

The problem is exacerbated, doctors say, because the disorder, which tends to develop in adolescence or early adulthood, is usually not diagnosed right away. Many primary-care doctors are not aware of it or have never seen a case firsthand. Dr. Siegel estimates that the average time between actual onset and diagnosis is five to seven years.

Part of the reason, he said, is that poor sleep is so common that many doctors do not think of narcolepsy.

''I was always falling asleep in class, and I thought it was my own fault,'' said Bill Baird, 66, of Monterey, Calif., whose narcolepsy was undiagnosed for years. ''I thought everybody got as sleepy as I did, but other people were able to resist it more. No one ever suggested it might be a medical problem.''

But narcolepsy goes far beyond normal sleepiness: researchers compare the disorder to the way nonsufferers feel if they have not slept for two full days. Despite their sleepiness, however, people with narcolepsy often have trouble getting a good night's rest.

Most people without narcolepsy sleep about 90 minutes before slipping into rapid eye movement, or REM, sleep, which is when dreams occur. In contrast, narcoleptics fall almost immediately into REM sleep and experience regular disruptions of their sleep cycle. In addition to sleepiness and attacks of muscle weakness, two other common symptoms are brief periods of paralysis while falling asleep or waking up, and hallucinatory experiences that can occur when a person is very sleepy but still technically awake.

''Often it's very scary,'' said Dr. Mignot. ''I have one patient who every night would see someone coming and strangling him.''

The current standard of care includes prescribing stimulants to help the sufferer stay awake during the day and certain antidepressants with a sedating effect to help bring on sleep at night.

Two years ago, a new drug, modafinil, was approved and was thought to have fewer side effects than stimulants like amphetamines. It has been popular with doctors and patients alike, although some doctors say it is not necessarily more effective than other medications.

While these drugs can help alleviate the symptoms, they do not address the underlying problem of hypocretin deficiency. The same applies to the GHB drug, Xyrem, which allows narcoleptics to fall into the deep nighttime sleep that they almost never experience on their own.

GHB has a checkered history, however. Its association with dance club deaths and date rapes has led the federal government and many states to classify it as among the most dangerous recreational drugs. It also discouraged many pharmaceutical companies from studying GHB, even though its potential benefits have long been known.

Orphan Medical says it is developing a stringent distribution system that will make it hard for anyone without a legitimate need to obtain Xyrem. Rather than distributing it to retail outlets, the company plans to stock Xyrem at a central pharmacy and fulfill subscriptions by mailing out the drug.

''This is a controlled substance that needs to be handled very carefully,'' said Dave Folkens, a spokesman for Orphan Medical.

Narcoleptics are eagerly awaiting the drug agency's final approval. But the long delay in bringing the drug to market does not necessarily surprise them.

Because the disorder is not life-threatening and does not affect a huge number of sufferers, they say, researchers and drug companies have not generally shown much interest in studying it and the general public has not clamored for progress in treating it.

''It hasn't been a priority,'' Mr. Baird said. ''People may not really understand what narcolepsy is, so there's a need for increasing public awareness, but there's no famous movie star promoting it.''

Correction: January 10, 2002, Thursday Because of an editing error, an article in Science Times on Tuesday about progress in treating the sleep disorder narcolepsy misstated the age of Bill Baird, a man from Monterey, Calif., whose case went undiagnosed for years. He is 63, not 66.